Since the first report of solid-phase synthesis of peptides by Merrifield in 1962, several applications of using solid matrices have evolved over the past 50 years. For example, solid-phase synthesis is now routinely employed for the synthesis and manufacture of macromolecules such as peptides, carbohydrates, and oligonucleotides. Also, several organic reactions are routinely performed in solution phase employing reagents that are covalently bound to solid matrix. Following the reaction, the matrix containing the reagent is simply filtered off from the reaction medium enabling partial purification of the desired product from the solution. In another application, compounds attached to solid matrices that carry acidic and basic moieties are employed as “scavengers” of basic and acidic reagents respectively from reaction media.
Several catalysts employed in organic synthesis are often employed as solid matrix. Compounds attached to solid matrices are also employed as sensors in detection devices. In yet another application, drug molecules attached to solid matrices are used as delivery systems for topical and systemic administration of drugs.
Macromolecules such as oligonucleotides as antisense compounds and as agents of RNA interference are synthesized and manufactured routinely using solid-phase synthesis. In this case, the first nucleotidic or amino acid residue (also referred to as the leader building block) is covalently attached to the solid matrix via a linker arm. The subsequent addition of monomeric units to the leader block is carried out on the solid matrix. Upon completion of the assembly of the macromolecule, the matrix is treated with a chemical reagent that cleaves the linker arm of the leader block thereby releasing the macromolecule into solution.
The attachment of chemical moiety to the matrix is a very important step for various applications of the matrices. Usually the chemical moiety is employed as a solution, which is then contacted with the matrix with and without the aid of a catalyst or other reagent. Since this is a biphasic reaction involving solid and liquid matrix, reaction times can often vary from several hours even into days before complete reaction occurs. Consequently, the initial attachment of the chemical moiety to the matrix is the rate-limiting step. Furthermore, an important parameter for the use of any matrix is the “loading of the support” (expressed as micromol/g) with the chemical moiety. A low loading would necessitate the use of larger amounts of the matrix to accomplish a desired application objective. This results in substantial increase in cost. The loading protocols employ hazardous solvents and reagents and takes long reaction times. The commonly employed loading processes are also inefficient since, often incomplete reaction results in “uncapped” functionalities on the solid matrix. Thus e.g., when a loaded matrix is employed in solid-phase synthesis, uncapped functionalities on the solid matrix would interfere with the subsequent synthetic steps thereby decreasing the overall yield of the desired product. Thus an additional “capping step” needs to be employed before the matrix can be used in synthesis.
Clearly, efficient processes for attaching chemical moieties to different types of matrices will be of great value in the use of the matrices for different applications.